PRECAUTIONS
GENERAL
Patients with TG levels greater than 300 mg/dL were excluded from WelChol® clinical trials. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL.
In non-clinical safety studies, rats administered colesevelam at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. WelChol® did not induce any clinically significant reduction in the absorption of vitamins A, D, E, or K during clinical trials of up to one year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat soluble vitamin deficiencies.
The safety and efficacy of WelChol® in patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal tract surgery have not been established. Consequently, caution should be exercised when WelChol® is used in patients with these gastrointestinal disorders.
INFORMATION FOR THE PATIENT
WelChol® may be taken once per day with a meal, or taken twice per day in divided doses with meals. Patients should be directed to take WelChol® with a liquid and a meal, and adhere to their NCEP-recommended diet. Patients should tell their physicians if they are pregnant, are intending to become pregnant, or are breastfeeding.
LABORATORY TESTS
Serum total-C, LDL-C and TG levels should be determined periodically based on NCEP guidelines to confirm favorable initial and adequate long-term responses.
DRUG INTERACTIONS
WelChol® has been studied in several human drug interaction studies in which it was administered with a meal and the test drug. WelChol® was found to have no significant effect on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, and warfarin. WelChol® decreased the Cmax and AUC of sustained-release verapamil (Calan SR® ) by approximately 31% and 11%, respectively. Since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear. In clinical studies, co-administration of WelChol® with atorvastatin, lovastatin, or simvastatin did not interfere with the lipid-lowering activity of the HMG-CoA reductase inhibitor. Other drugs have not been studied. When administering other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy, physicians should consider monitoring drug levels or effects.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
A 104-week carcinogenicity study with colesevelam (WelChol® ) was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam (WelChol® ) in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).
Colesevelam and four degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The four degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with two of the four degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other two degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.
Colesevelam did not impair fertility in rats at doses of up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).
PREGNANCY
PREGNANCY CATEGORY B
Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Requirements for vitamins and other nutrients are increased in pregnancy. The effect of WelChol® on the absorption of vitamins has not been studied in pregnant women.
PEDIATRIC USE
The safety and efficacy of colesevelam (WelChol® ) have not been established in pediatric patients.
GERIATRIC USE
There is no evidence for special considerations when colesevelam (WelChol® ) is administered to elderly patients.
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